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https://dora.health.qld.gov.au/qldresearchjspui/handle/1/3170| Title: | Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients | Authors: | Mitchell, Richard Pillay, Bethany A. Avery, Danielle T. Smart, Joanne M. Cole, Theresa Choo, Sharon Chan, Damien Gray, Paul E. Frith, Katie Phan, Tri Giang Wong, Melanie Campbell, Dianne E. Hsu, Peter Ziegler, John B. Alvaro, Frank Picard, Capucine Bustamante, Jacinta Neven, Benedicte Cant, Andrew J. Uzel, Gulbu Arkwright, Peter D. Casanova, Jean-Laurent Su, Helen C. Freeman, Alexandra F. Shah, Nirali Hickstein, Dennis D. Tangye, Stuart G. Ma, Cindy S. Peake, Jane |
Issue Date: | 2019 | Source: | 5 , 2019 | Journal: | JCI insight | Abstract: | Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αβ T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.Science. 2002 Nov 22;298(5598):1630-4. (PMID: 12446913); J Immunol Methods. 2003 Oct 1;281(1-2):65-78. (PMID: 14580882); J Allergy Clin Immunol. 2004 Mar;113(3):395-400. (PMID: 14758340); Bone Marrow Transplant. 2004 Jul;34(1):1-12. (PMID: 15156163); Bone Marrow Transplant. 2004 Oct;34(7):595-602. (PMID: 15300228); J Immunol. 2006 Feb 1;176(3):1506-16. (PMID: 16424179); Nat Rev Immunol. 2006 Oct;6(10):741-50. (PMID: 16977339); N Engl J Med. 2009 Nov 19;361(21):2046-55. (PMID: 19776401); Nat Immunol. 2009 Dec;10(12):1283-91. (PMID: 19898472); Blood. 2010 Jan 21;115(3):519-29. (PMID: 19965666); J Allergy Clin Immunol. 2009 Dec;124(6):1289-302.e4. (PMID: 20004785); Bone Marrow Transplant. 2011 Apr;46(4):552-6. (PMID: 20622910); Klin Padiatr. 2010 Nov;222(6):351-5. (PMID: 21058221); Blood. 2011 Mar 17;117(11):3243-6. (PMID: 21273302); J Allergy Clin Immunol. 2011 Aug;128(2):420-22.e2. (PMID: 21546070); Eur J Immunol. 2011 Dec;41(12):3423-35. (PMID: 21969276); J Exp Med. 2011 Oct 24;208(11):2305-20. (PMID: 22006977); Blood. 2011 Dec 22;118(26):6824-35. (PMID: 22039266); Pediatr Transplant. 2012 Jun;16(4):398-9. (PMID: 22248482); Clin Immunol. 2012 Jun;143(3):266-72. (PMID: 22534316); Nat Immunol. 2012 May 13;13(6):612-20. (PMID: 22581261); Pediatr Hematol Oncol. 2012 Oct;29(7):585-94. (PMID: 22897717); J Allergy Clin Immunol. 2013 Mar;131(3):840-8. (PMID: 23380217); Blood. 2013 Sep 19;122(12):2052-61. (PMID: 23929855); Front Immunol. 2014 Feb 18;5:65. (PMID: 24600453); Clin Immunol. 2014 May-Jun;152(1-2):111-4. (PMID: 24667686); J Allergy Clin Immunol. 2014 Jul;134(1):221-3. (PMID: 24698323); J Allergy Clin Immunol. 2014 Jun;133(6):1667-75. (PMID: 24797421); N Engl J Med. 2014 Jul 31;371(5):434-46. (PMID: 25075835); J Allergy Clin Immunol. 2014 Oct;134(4):935-943.e15. (PMID: 25109802); J Allergy Clin Immunol. 2014 Dec;134(6):1365-1374. (PMID: 25218284); Curr Opin Pediatr. 2014 Dec;26(6):704-12. (PMID: 25321844); J Exp Med. 2014 Dec 15;211(13):2549-66. (PMID: 25422492); J Clin Immunol. 2015 Feb;35(2):189-98. (PMID: 25627830); Biol Blood Marrow Transplant. 2015 Jun;21(6):1037-45. (PMID: 25636378); J Allergy Clin Immunol. 2015 Aug;136(2):402-12. (PMID: 25724123); J Exp Med. 2015 Jun 1;212(6):855-64. (PMID: 25941256); J Allergy Clin Immunol. 2015 Oct;136(4):993-1006.e1. (PMID: 26162572); Nat Rev Immunol. 2015 Aug;15(8):486-99. (PMID: 26205583); J Clin Immunol. 2015 Oct;35(7):604-9. (PMID: 26433589); Turk J Pediatr. 2015 Jan-Feb;57(1):112-5. (PMID: 26613234); J Allergy Clin Immunol. 2016 Jun;137(6):1895-1898.e5. (PMID: 26827248); J Allergy Clin Immunol. 2016 Sep;138(3):852-859.e3. (PMID: 27130861); Nat Rev Dis Primers. 2015 Oct 29;1:15061. (PMID: 27189259); J Allergy Clin Immunol. 2016 Nov;138(5):1384-1394.e2. (PMID: 27350570); J Allergy Clin Immunol. 2017 Mar;139(3):933-949. (PMID: 27554822); Nat Immunol. 2016 Nov;17(11):1291-1299. (PMID: 27618553); J Allergy Clin Immunol Pract. 2016 Nov - Dec;4(6):1239-1242.e1. (PMID: 27641484); J Allergy Clin Immunol. 2016 Oct;138(4):957-969. (PMID: 27720020); Clin Immunol. 2017 May;178:39-44. (PMID: 27890707); J Allergy Clin Immunol. 2017 Nov;140(5):1388-1393.e8. (PMID: 28192146); Biol Blood Marrow Transplant. 2017 Jun;23(6):980-990. (PMID: 28288951); J Allergy Clin Immunol. 2018 Mar;141(3):1028-1035. (PMID: 28606585); Pediatr Transplant. 2017 Nov;21(7):null. (PMID: 28664550); Front Immunol. 2017 Jul 24;8:847. (PMID: 28791010); J Immunol. 2017 Aug 9;:null. (PMID: 28794229); Front Immunol. 2017 Aug 09;8:944. (PMID: 28848550); Clin Immunol. 2017 Oct;183:263-265. (PMID: 28882618); Blood. 2017 Dec 21;130(25):2718-2727. (PMID: 29021228); J Clin I munol. 2018 Jan;38(1):96-128. (PMID: 29226302); Bone Marrow Transplant. 2018 Mar;53(3):339-343. (PMID: 29269803); Front Immunol. 2017 Dec 21;8:1861. (PMID: 29312341); Blood Adv. 2018 Feb 27;2(4):401-413. (PMID: 29472447); J Exp Med. 2018 Apr 2;215(4):1009-1022. (PMID: 29549114); Biochem Biophys Res Commun. 2018 Jun 18;501(1):92-99. (PMID: 29702092); Blood. 2018 Jun 28;131(26):2967-2977. (PMID: 29728406); J Allergy Clin Immunol. 2019 Jan;143(1):276-291.e6. (PMID: 29800648); Blood. 2018 Oct 25;132(17):1737-1749. (PMID: 30154114); J Allergy Clin Immunol Pract. 2019 Mar;7(3):848-855. (PMID: 30391550); Immunol Rev. 2019 Jan;287(1):241-252. (PMID: 30565242); Immunol Rev. 2019 Jan;287(1):9-19. (PMID: 30565250); Immunol Cell Biol. 2019 Apr;97(4):389-402. (PMID: 30779216); J Allergy Clin Immunol. 2019 Jun;143(6):2302-2305. (PMID: 30796983); Pediatrics. 1968 Mar;41(3):600-11. (PMID: 4171004); Lancet. 1968 Mar 9;1(7541):503-6. (PMID: 4171200); Lancet. 1968 Dec 28;2(7583):1366-9. (PMID: 4177932); J Immunol. 1981 Oct;127(4):1307-13. (PMID: 6974188); Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9488-93. (PMID: 9689107). Linking ISSN: 23793708. Subset: MEDLINE; Grant Information: United States HHMI Howard Hughes Medical Institute Date of Electronic Publication: 2019 Apr 25. ; Original Imprints: Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- | DOI: | 10.1172/jci.insight.127527 | Resources: | https://search.ebscohost.com/login.aspx?direct=true&AuthType=ip,athens&db=mdc&AN=31021819&site=ehost-live | Keywords: | Stem cell transplantation*;Hematopoietic Stem Cell Transplantation*B-Lymphocytes/*immunology;Guanine Nucleotide Exchange Factors/*deficiency;Job Syndrome/*therapy;T-Lymphocytes/*immunology;Adolescent;Adult;Cell Differentiation/genetics;Cell Differentiation/immunology;Child;Child, Preschool;Humans;Immunoglobulin E/blood;Immunology*;Infectious disease*;Immunoglobulin E/immunology;Job Syndrome/blood;Job Syndrome/genetics;Job Syndrome/immunology;Lymphocyte Activation/genetics;Treatment Outcome;Young Adult;Adaptive immunity*;Cellular immune response* | Type: | Article |
| Appears in Sites: | Children's Health Queensland Publications |
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